Role of Keratinocytes in Sensitive Skin

Abstract

Sensitive skin is a clinical syndrome defined by the occurrence of unpleasant sensations such as burning, stinging, tingling, pricking, or itching in response to various normally innocuous physical, chemical, and thermal stimuli. These particular symptoms have led the consideration of a potential dysfunction of the intra-epidermal nerve fibers (IENF) that are responsible for pain, temperature, and itch perception. This neuronal hypothesis has just been reinforced by recent studies suggesting that sensitive skin could become assimilated to small fiber neuropathy. Meanwhile, the involvement of keratinocytes, the pre-dominant epidermal cell type, has so far mainly been considered because of their role in the epidermal barrier. However, keratinocytes also express diverse sensory receptors present on sensory neurons, such as receptors of the transient receptor potential (TRP) family, including Transient Receptor Potential Vallinoid 1 (TRPV1), one of the main transducers of painful heat which is also involved in itch transduction, and Transient Receptor Potential Vallinoid 4 (TRPV4) which is depicted as a heat sensor. While TRPV1 and TRPV4 are expressed both by sensory neurons and keratinocytes, it has recently been demonstrated that the specific and selective activation of TRPV1 on keratinocytes is sufficient to induce pain. Similarly, the targeted activation of keratinocyte-expressed TRPV4 elicits itch and the resulting scratching behavior. So, contrary to classical conception, the IENF are not the exclusive transducers of pain and itch. In light of these recent advances, this review proposes to consider the putative role of epidermal keratinocytes in the generation of the unpleasant sensations characteristic of sensitive skin syndrome.

Keywords: TRP; itch; keratinocyte; pain; sensitive skin; sensory neuron.

Figure 1

Main exogenous stimuli triggering the unpleasant sensory perceptions that characterize sensitive skin syndrome.

Figure 2

Intra-epidermal nerve fibers. Intra-epidermal nerve fibers, classified as C- and Aδ-fibers, unmyelinated, and thickly myelinated respectively, are conventionally described as the exclusive sensors for temperature, pain, and itch. Aδ-fibers lose their myelin sheath when crossing the basement membrane.

Figure 3

Identified exogenous stimuli and the corresponding keratinocyte sensory receptors triggering pain or itch in mouse models. (A) Chemical stimuli. Capsaicin can induce pain through the activation of keratinocyte-expressed TRPV1. By extension this process probably concerns H+ ions. (B) Chemical stimuli. Histamine and endothelin-1 activate TRPV4 through their respective receptors. Downstream TRPV4 activation induces itch. (C) Thermal stimuli. TRPV1 is also the main transducer of noxious heat. (D) Physical stimuli. UVB activate keratinocyte-expressed TRPV4 to induce pain. (E) Like intense pressure via not yet identified mechanoreceptor(s).

Figure 4

Exogenous painful stimuli. Correspondence between keratinocytes and sensitive skin syndrome. Epidermal keratinocytes can transduce nociceptive information from exogenous stimuli belonging to the three categories of stimuli identified as provoking the unpleasant sensory perceptions characteristic of sensitive skin syndrome.